Given the tremendous success in vaccination against infectious diseases, using tumor cells as immunogens to induce anti-tumor immunity is an attractive strategy to combat various human cancers. However, tumor cells themselves are usually poor immunogen. Possible reasons include down regulation of MHC molecules, lack of costimulatory molecules and unable to process and present antigen on cell surface. Numerous efforts have been made to transfect tumor cells with cDNAs of MHC molecule, costimulatory molecules, or particular cytokines to increase their immunogenicity and promote immune response (1). It has also been shown that hybrid between tumor cells and antigen-presenting cells (APCs) can induce strong anti-tumor immunity. Although many of these strategies have yielded promising results in animal models, clinical trials in humans are generally disappointing.
Dendritic cells (DCs) are unique high-potent antigen-presenting cells and capable of sensitizing naive CD4+ T cells and CD8+ T cells. With isolation and bulk propagation of DCs in vitro being available, great efforts have been made to use DCs in various immunization strategies (3). Immunization with DCs pulsed with tumor antigens or antigen-driven peptides can generate tumor-specific immune responses and anti-tumor effects (4,5). Since only a limited number of tumor-associated or tumor-specific antigens have been identified and shown recognized by cytotoxic T lymphocytes (CTLs), tumor-derived protein extracts or RNA have been used as the source of antigen (6,7). An additional potential advantage for these types of strategies is that they might induce immune response against multiple epitopes of tumors. However, the antigen-presenting pathways under these situations and the efficiency in priming both CD4+ and CD8+ T cells remain unclear.
Interleukin 18 (IL-18) was initially identified as a cytokine that facilitates the production of interferon-γ (IFN-γ) induced by endotoxin. It is an essential factor for IFN-γ production in response to microbial agents, and can act together with IL-12 in promoting the generation of IFN-γ-producing Th1 cells. In IL-18-deficient mice, there are defects in generation of Th1 response. These results indicate that IL-18 plays an essential role in inducing Th1 response in vivo. Consistent with the notion that Th1 cells are involved in anti-tumor immunity, administrations of IL-18 with or without IL-12 have significant anti-tumor effects (8, 9). However, administration of IL-18 is associated with septic shock-like severe toxicity that prevents its application (10). Interestingly, it was found that immunization with tumor cells expressing IL-18 with or without IL-12 could generate stronger antitumor effect than immunization with un-transfected tumor cells (11), indicating that vaccine expressing IL-12 and IL-18 may be used in inducing anti-tumor immunity.
Therefore, it has long been needed in the art to develop an effective, specific tumor vaccine with little or no side effect.